Lyme Disease (LD) is an important tick-borne disease in man and animals caused by the spirochete Borrelia burgdorferi. This organism causes a wide spectrum of symptoms and disease of multiple tissues, particularly musculoskeletal, cardiac and nervous systems. Despite its frequency, the pathogenesis of LD is poorly understood because of its usually non-fatal nature and the inappropriateness of unnecessary invasive procedures. This project will utilize a recently discovered laboratory mouse model of LD to explore LD pathogenesis. Major objectives include examination of the long-term course of B. burgdorferi infection in genetically susceptible and resistant strains of mice. The kinetics of spirochete dissemination, tissue localization and persistence will be examined by light microscopy, microbiology, immunohistochemistry and nucleic acid hybridization. Host inflammatory and immune responses to B. burgdorferi as well as effect of infection upon immune responsiveness will be examined with a number of approaches, including antigen-specific and mitogen-driven proliferative assays, adoptive transfer studies, and in situ examination of arthritisassociated cell types by immunohistochemistry. Changes in the spirochete following persistent infection will also be examined, including antigenic, genetic and pathogenic variation. The mechanisms of early arthritogenesis will be examined in susceptible and resistant genotypes, including differences in neutrophil, macrophage, natural killer cell and synoviocyte function. The broad array of immunogenetic techniques and reagents available to investigations on laboratory mice will provide important new insight into LD pathogenesis.